1. Field of the Invention
The present invention relates generally to the field of cancer treatment. More particularly, it concerns methods of generating DHA-containing lipid nanoparticles and their use in the treatment of cancer.
2. Description of Related Art
In recent years, the dietary benefits of omega-3 polyunsaturated fatty acids (ω-3 PUFA) have not only been heralded for improving cardiovascular health, but also for preventing cancer. Numerous population ecological studies have shown that a high per capita consumption of cold water fish (a high source of ω-3 PUFAs) correlates with lower risk of cancer (Hursting et al., 1990; Caygill et al. 1996; Sasaki et al., 1993; Sasazuki et al.; 2011; Sawada et al., 2012). The active anti-cancer components in fish oil are the PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Animal studies also support this inverse association, as they have shown that high dietary intake of ω-3 PUFAs can markedly impede experimental carcinogenesis (Sasazuki et al.; 2011; Sawada et al., 2012; Berquin et al., 2007; Iwamoto et al., 1998; Braden et al., 1986; Rose et al., 1993). Collectively, these epidemiologic and preclinical studies indicate that high dietary ω-3 PUFAs can antagonize the initiation and early progression of cancer in situ.
It is less clear what role or benefit ω-3 PUFAs may have in the treatment of pre-existing tumors. To date, many papers have demonstrated the dose-dependent cytotoxicity of ω-3 PUFAs towards various cancer cells in culture (Kang et al., 2010; Lim et al., 2009; Lindskog et al., 2006). However, the local doses of ω-3 PUFAs used to elicit these anticancer effects in culture are difficult, if not impossible, to achieve through dietary consumption (Conquer and Holub, 1998). This likely explains why the few studies that attempted to treat established tumors through dietary consumption of ω-3 PUFAs reported inconsistent results with only modest effects (Gleissman et al., 2010; Noguchi et al., 1997; Swamy et al., 2008). Direct intravascular administration of ω-3 PUFAs is not a feasible option due to their poor aqueous solubility and propensity to form emboli (Gupta et al., 2007; Namani et al., 2007). Even for the cell culture experiments mentioned above, organic solvents, such as ethanol or dimethyl sulfoxide, were required to solubilize the ω-3 PUFAs in cell culture media. Alternatively albumin can be used as a physiological transporter for ω-3 PUFAs, however, there are some concerns that albumin may protect cancer cells against ω-3 PUFA-induced cytotoxicity (Kanno et al., 2011; Roche et al., 2008). Fish oil-based emulsions used for parenteral nutrition (e.g., Omegaven) can transport large amounts of ω-3 PUFAs in the plasma. However, their large heterogeneous size (diameters >200 nm), rapid clearance by the mononuclear phagocyte system (MPS) and poor sensitivity to lipoprotein lipase limit their efficacy to deliver ω-3 PUFAs to tumors (Gura, 2006; Lutz et al., 1989; Oliveira et al., 1997).